A Single 17D Yellow Fever Vaccination Provides Lifelong Immunity; Characterization of Yellow-Fever-Specific Neutralizing Antibody and T-Cell Responses after Vaccination

Abstract

IntroductionPrompted by recent amendments of Yellow Fever (YF) vaccination guidelines from boost to single vaccination strategy and the paucity of clinical data to support this adjustment, we used the profile of the YF-specific CD8+ T-cell subset profiles after primary vaccination and neutralizing antibodies as a proxy for potentially longer lasting immunity.Methods and FindingsPBMCs and serum were collected in six individuals on days 0, 3, 5, 12, 28 and 180, and in 99 individuals >10 years after YF-vaccination. Phenotypic characteristics of YF- tetramer+ CD8+ T-cells were determined using class I tetramers. Antibody responses were measured using a standardized plaque reduction neutralization test (PRNT). Also, characteristics of YF-tetramer positive CD8+ T-cells were compared between individuals who had received a primary- and a booster vaccination. YF-tetramer+ CD8+ T-cells were detectable on day 12 (median tetramer+ cells as percentage of CD8+ T-cells 0.2%, range 0.07–3.1%). On day 180, these cells were still present (median 0.06%, range 0.02–0.78%). The phenotype of YF-tetramer positive CD8+ T-cells shifted from acute phase effector cells on day 12, to late differentiated or effector memory phenotype (CD45RA-/+CD27-) on day 28. Two subsets of YF-tetramer positive T-cells (CD45RA+CD27- and CD45RA+CD27+) persisted until day 180. Within all phenotypic subsets, the T-bet: Eomes ratio tended to be high on day 28 after vaccination and shifted towards predominant Eomes expression on day 180 (median 6.0 (day 28) vs. 2.2 (day 180) p = 0.0625), suggestive of imprinting compatible with long-lived memory properties. YF-tetramer positive CD8+ T-cells were detectable up to 18 years post vaccination, YF-specific antibodies were detectable up to 40 years after single vaccination. Booster vaccination did not increase titers of YF-specific antibodies (mean 12.5 vs. 13.1, p = 0.583), nor induce frequencies or alter phenotypes of YF-tetramer+ CD8+ T-cells.ConclusionThe presence of a functionally competent YF-specific memory T-cell pool 18 years and sufficient titers of neutralizing antibodies 35–40 years after first vaccination suggest that single vaccination may be sufficient to provide long-term immunity.

Comprehensive analysis of antiviral adaptive immunity formation and reactivation down to single-cell level

“…The response to a single immunodominant epitope can contribute to up to 60% of the total response It was previously shown that in HLA-A02 donors the NS4B 214−222 LLWNGPMAV immunodominant epitope elicits the strongest CD8+ T-cell response [3,5,7,15]. Using an HLA-A02-pMHC-dextramer, we isolated NS4Bspecific CD8+ T-cells from both donors ( Fig.…”

“…An essential feature of effective vaccination is the formation of immune memory. Although most of the effector cells die shortly after viral clearance, YF-specific T-cells could be found in the blood of vaccinated individuals years [3,7,8,11] and even decades after vaccination [14,15]. While the immune response to the primary vaccination has been much studied, there is only limited data on the response to the booster vaccination with YFV17D.…”

T Lymphocytes as Measurable Targets of Protection and Vaccination Against Viral Disorders

“…Increased CD8 þ T cell proliferation correlates directly with the levels of virus genomes in plasma, which peaks once virus is eliminated . CD8 þ T cell clones responding to 17D differentiate into central memory and effector memory subpopulations (Dewitt et al, 2015) and are still detectable 25 years following vaccination (Wieten et al, 2016). 17D-specific CD8 þ T cells respond to epitopes contained from every protein product generated by the 17D polyprotein, and upon peptide restimulation, these 17D-specific CD8 þ T cells have activated cytotoxic profiles including increased expression of IFN-g, TNF-a, and MIP1-b and IL-2 granzyme B and CD107a (Blom et al, 2013;Akondy et al, 2009) but are not exhausted and retain long-lived memory and polyfunctional phenotypes for at least 2 years following 17D rechallenge (Akondy et al, 2009).…”

The Importance of Understanding MHC-I Diversity in Nonhuman Primate Models of Human Infectious Diseases

“…One of the most important genome loci involved in immunity to pathogens is the major histocompatibility complex (MHC). This region encodes the classical MHC-I and MHC-II genes as well as non-classical MHC genes such as MHC-E, which has received much recent attention (Davis et al, 2016; Hansen et al, 2016; Pietra et al, 2010; van Meijgaarden et al, 2015) and others. It also contains genes that encode proteins involved in a number of other immunological processes, such as the Transporter associated with Antigen Processing (TAP) and Tumor Necrosis Factor alpha (TNF-α) (Horton et al, 2004; Shiina et al, 2009).…”

“…The ultimate goal of vaccines in general is to prevent infection at the port of entry, suggesting that neutralizing antibodies should be the most critical immunological component of a vaccine. However, one of the most effective vaccines ever created, the Yellow Fever vaccine 17D, induces a broad immunological response that includes antibodies and TCD8+ cells (Muyanja et al, 2014; Querec et al, 2009; Wieten et al, 2016), all of which likely contribute to viral prevention and clearance. In addition, a number of vaccines could be enhanced by induction of effective TCD8+ cells, which can target all viral proteins, rather than just the envelope glycoprotein, the predominant target of neutralizing antibodies.…”